Project Summary Levodopa-induced dyskinesia (LID) commonly develops during long-term treatment of Parkinson's Disease, affecting most patients after 5-10 years of treatment. The abnormal involuntary movements eventually limit the levodopa dose, and often patients require deep brain stimulation (DBS). The neural mechanisms of LID are not fully understood, but the leading hypothesis is that levodopa triggers aberrant activity in the input nucleus of the basal ganglia, the striatum. Even in the advanced stages of disease, however, levodopa continues to have both therapeutic and pathological effects, promoting normal movement and abnormal involuntary movements. This clinical observation led us to hypothesize that within the striatum, distinct populations of neurons correlate with dyskinetic versus prokinetic (therapeutic) effects of levodopa. Our pilot studies indicate that a substantial fraction of striatal neurons show strong correlations in their activity with either increased normal movement, or dyskinesia, and few neurons correlate with both responses. By understanding the intrinsic and synaptic properties that distinguish these two groups of striatal neurons, subsequent drug development might be able to selectively target movement neurons, relieving motor symptoms of Parkinson's Disease, without affecting dyskinetic neurons and avoiding dyskinesia. Using a combination of awake-behaving single-unit recordings, optogenetics, and ex vivo slice recordings in a mouse model of LID, this proposal aims to (1) characterize striatal direct pathway neuronal responses to levodopa, including identifying units whose firing correlates with dyskinesia, (2) determine whether these neurons cause dyskinesia, and (3) identify the underlying cellular mechanisms (alterations in intrinsic excitability and/or excitatory inputs) that distinguish them. To test the causal role of dyskinesia-correlated striatal units in dyskinesia, we will use the novel transgenic tool, Targeted Recombination in Active Populations (TRAP), which allows capture and subsequent manipulation of previously activated neurons. These studies will provide the first detailed look at whether levodopa triggers therapeutic and dyskinetic effects through two different striatal effector populations, and begin to dissect the underlying cellular and synaptic mechanisms. !